Activation of the stress pathway and engagement of the apoptotic program represent two fundamental cellular responses to damage. Coordination of the cellular stress response is mediated by the transcriptional activity of heat shock factor-1 (HSF-1), the primary regulator of heat shock protein expression. Stress-induced regulation of death ligand expression represents a paradigm for the transcriptional regulation of apoptosis with implications in the homeostatic regulation of the immune system. This proposal examines the role of heat shock factor-1 (HSF-1) in immune regulation as a consequence of its effects on the expression of death ligands. We will determine (a) if HSF-1 regulates the induction and consequences of FasL expression in vivo. The physiological consequences of altered death ligand expression are best exemplified by the elevation of FasL in (i) activation induced cell death (AICD) and (ii) peripheral deletion in T lymphocytes. We propose to utilize HSF-1-/- mice and cells harvested from these animals to determine the role of HSF-1 in the upregulation of FasL expression and sensitization of cells to Fas-mediated apoptosis that is associated with AICD and peripheral deletion (b) which of the signaling pathways activated as a consequence of T cell receptor activation impact directly on the transcriptional activity of HSF-1 to modulate death ligand expression and (c) the precise mechanism of HSF-1-mediated transcriptional regulation of FasL expression with emphasis on its interaction with NFAT. To that end, this aim will identify a non-heat shock target for HSF-1 and significantly, a novel cooperative interaction between NFAT and HSF-1. Ultimately, this aim will address if the transcriptional activity of HSF-1 represents a fundamental stress-responsive mechanism engaged to modulate cellular sensitivity to damage via regulation of the expression of the death ligands. In summary, we would like to propose that the ubiquitous activation of HSF-1 in response to multiple stressors represents a fundamental mechanism to coordinately regulate a variety of non-heat shock target genes including those intimately involved in the regulation of apoptosis. Co-operative interaction of HSF-1 with other transcription factors, one of which may be NFAT, could serve to differentially regulate gene expression according to the nature and duration of the stress and potentially in a cell type specific manner. The studies outlined will dissect those signals generated as a consequence of T cell receptor activation that impact on HSF-1 activity to regulate death ligand expression and sensitivity to apoptosis and by doing so will define a novel regulatory pathway involved in T cell function and maintenance of immune homeostasis.